A. Field of the Invention
The present invention relates to analgesic compositions and more specifically relates to synergistic combinations of acetaminophen and an analgesic, anti-inflammatory agent selected from the group consisting of D-phenylalanine, DL-phenylalanine, D-leucine, DL-leucine and hydrocinnamic acid.
Acetaminophen is a well know, and widely used analgesic and antipyretic agent, sold by various companies under the trade marks "Tylenol", "Datril", "Panedol", "Anacin-3", etc. It is currently estimated that McNeil's Tylenol brand of acetaminophen accounts for approximately 30% of the over-the-counter analgesic market.
While aspirin is widely used for the relief of pain, fever and inflammation, and is considered to be the model for non-steroidal anti-inflammatory agents, many people are unable to take aspirin because of its gastrointestinal side effects, and others are unable to take the drug because of sensitivity or allergic reactions. In particular, patients suffering from upper gastrointestinal disorders such as ulcers, gastritis and hiatus hernia, inflammatory bowel disease such as ulcerative colitis, or who exhibit hemostatic disturbances (including anticoagulant therapy), or suffer from asthma, or who have exhibited a sensitivity to aspirin, must take acetaminophen for the relief of mild pain to moderate pain and fever. In addition, in view of the suggested link between aspirin and Reyes syndrome in children, it is generally considered to be unsafe to give a child aspirin to reduce a fever due to cold or flu. Thus, acetaminophen has become an increasingly popular analgesic, anti-pyretic agent both in children and adults because of its' lack of side effects generally associated with aspirin.
While this valuable therapeutic agent has rarely been found to produce any side effects, it has several drawbacks. First, it does not exhibit anti-inflammatory activity, and thus does not relieve inflammation associated with arthritis and other inflammatory conditions, although it is used to relieve pain where aspirin and other non-steroidal anti-inflammatory agents can not be tolerated.
Further, large doses of acetaminophen have been associated with hepatic toxicity, and daily dosages are generally limited to one or two capsules containing 325-500 mg of acetaminophen every four to six hours, and a maximum total daily dosage of 4,000 mg.
While acetaminophen is suitable for controlling mild pain, it generally is not effective in cases of acute or chronic moderate to severe pain associated with oral or other surgery, chronic back pain, cancer, and the like. In such cases, controlled drugs such as codeine alone or in combination with aspirin or acetominophen, or Darvon (propoxyphene), Demerol, morphine, and the like are generally employed. Because of the abuse potential of the control drugs, or narcotics, as well as the undesirable side effects associated therewith, there has been a longstanding need to provide improved analgesic agents which are as safe as acetaminophen, but which have enhanced analgesic properties.
In recent years, an entirely new class of analgesic, anti-inflammatory agents has been reported. Those agents are D-phenylalanine, D-leucine and hydrocinnamic acid. The compounds have are relatively non-toxic, with LD.sub.1 &gt;10 grams/kg in mice, and provide substantial relief from mild to moderate pain.
The analgesic activity of D-phenylalanine, D-leucine and hydrocinnamic acid is potentiated when those agents are co-administered with aspirin or other non-steroidal anti-inflammatory agent. However, this combination therapy is not suitable for patients who can not tolerate aspirin or other non-steroidal anti-inflammatory agents, and that a need therefore exists for analgesic agents which can be employed to treat acute or chronic moderate to severe pain, and which does not suffer from the side effects of aspirin and other non-steroidal anti-inflammatory agents, nor has the side effects and liabilities associated with narcotic analgesic agents. The present invention fulfills that need.
B. Prior Art
D-phenylalanine, DL-phenylalanine, D-leucine, DL-leucine and hydrocinnamic acid have been found to possess analgesic and anti-inflammatory activity. Their analgesic activity is significantly enhanced or potentiated by the co-administration of a prostaglandin synthetase inhibitor selected from the group consisting of aspirin or other non-steroidal anti-inflammatory, anti-pyretic agents such as ibuprofen and the like. See U.S. Pat. No. 4,439,452, issued Mar. 27, 1984 and commonly assigned, copending applications U.S. Ser. No. 657,681 filed Oct. 4, 1984 and U.S. Ser. No. 657,732, filed Oct. 4, 1984.
D-phenylalanine has also been reported to be useful in the treatment of depression at dosages of 50 or 100 mg per day and has been sold under the trademark "Deprenon" for the treatment of depression. See "Therapy of Depression by Phenylalanine" Arzneim Forsch, Vol. 25, NR1 (1975), and "Use of D-Phenylalanine in Parkinson's Disease, Arzneim Forsch, Vol. 26, NR4 (1976).
L-leucine and L-phenylalanine are also known to be useful as nutrients.
It has now surprisingly been found that while acetaminophen is not a peripheral prostaglandin synthetase inhibitor nor a non-steroidal anti-inflammatory, anti-pyretic agent, a synergistic analgesic effect is obtained when acetaminophen is coadministered with a compound selected from the group consisting of D-phenylalanine, DL-phenylalanine, D-leucine, DL-leucine and hydrocinnamic acid.